Bone pain - Genetics

Question 1

List the 8 hallmarks of cancer

Answer 1

1. Sustaining proliferative signalling
2. Evading growth suppressors
3. Avoiding immune destruction / resisting cell death
4. Enabling replicative immortality
5. Activating invasion and metastasis
6. Inducing angiogensis
7. Tumour-promoting inflammation (enabling charcteristics)
8. Genome instability and mutatin (enabling characteristics)

Question 2

One of the 8 cancer hallmarks is ‘sustaining proliferative signalling’. What does this mean?

Answer 2

• Cancer cells do not need stimulation from external signals (in the the form ofgrowth factors) to multiply
• They produce these signalsthemselves (autocrine signalling) by permanently activating the signalling pathways that respons to these signals or by destroying ‘off switches’ that prevents excessive growth from these signals (negative feedback)

Question 3

One of the 8 cancer hallmarks is ‘evading growth suppressors’. What does this mean?

Answer 3

• In cancer, tumour suppresor proteins are altered so tthat they don’t effectively prevent cell divison, even when the cell has severe abnormalities
• Cancer cells are able to bypass apoptosis

Question 4

One of the 8 cancer hallmarks is ‘Avoiding immune destruction/resisting cell death’. What does this mean?

Answer 4

Can avoid interaction with the body’s immune system via a loss of IL-33

Question 5

One of the 8 cancer hallmarks is ‘enabling replicative immortality’. What does this mean?

Answer 5

• Cells of the body have limited number of divisions before the cells becone unable to divide (senescene) or die (crisis) usually due to telomeres found at the end of chromosomes
• Cancer cells bypass this barrier by manipulating the enzyme telomerase to increase the length of telomeres

Question 6

One of the 8 cancer hallmarks is ‘Activating invasion and metastasis. What does this mean?

Answer 6

Cancer cells can break away from their site or organ of origin to invade surrounding tissue and metastasize to distant body parts

Question 7

One of the 8 cancer hallmarks is ‘inducing angiogenesis. What does this mean?

Answer 7

• Angiogenesis is the process by which new blood vessels are formed
• Cancer cells appear to be able to kickstart this process by reducing the production of factors that inhibit blood vessel production, and increasing the production of factors that promote angiogenesis
• This ensures the cancer cells recieve continual supply of oxygen and other nutrients

Question 8

One of the 8 cancer hallmarks is ‘tumour promoting inflammation’. What does this mean?

Answer 8

• Inflammation leads to angiogenesis and more of an immune response
• The degradation of extracellular matrix necesary to form new blood vessels increases the odds of metastasis

Question 9

One of the 8 cancer hallmarks is ‘genome instability and mutation’. What does this mean?

Answer 9

• Cancer cells generally have severe chromosomal abnormalities which worsen as the disease progress
• Small genetic mutattions are most likely what begin tumorigenesis, but once cells begin the breakage-fusion-bridge (BFB) cycle, they are able to mutate at much faster rates

Question 10

Cancer cells go under important heritable (cell to cell) changes e.g., dominant driver in oncogenes and recessive driver mutations in tumour supressor genes. These changes lead to a functional change in the operation of the cell. Describe 3 of these changes

Answer 10

1. A protein might be over expressed or under expressed
2. A protein might change its function
3. It might produce a change in the regulation of a pathway

Question 11

List the types of mutations that can occur

Answer 11

• Substitution
• Deletion
• Insertion
• Copy number change
• Break poitns/chromosal rearrangement/translocation - can lead to gene fusion

Question 12

What is a driver mutation?

Answer 12

A driver mutation is an alteration that gives a cancer cell a fundamental growth advantage for its neoplastic transformation

Question 13

What is a passanger mutation

Answer 13

A passanger mutation has no effect on the fitness of a clone but may be associated with a clonal expansion because it occurs in the same genome with a driver mutation

Question 14

What is an oncogene?

Answer 14

Proto-oncognes are genes that are essental for normal cell growth and differentiation. Mutations of proto-oncogenes form oncogenes that lead to unregulated cell growth.

Question 15

List 4 mutations that convert proto-oncogenes to oncogenes

Answer 15

1. Point mutation
2. Deletion
3. Gene amplification events
4. Chromosomal rearrangement - involving breakage and re-joining of the DNA helix

Question 16

Chromosomal translocation events often up-regulate an expression of oncogene by fusing the gene with a promotor region that is always switched on or active. What is the most famous chromosme of these?

Answer 16

Philadelphia chromosome

Question 17

What is the philadelphia chromosome famous for?

Answer 17

Chromosomal translocation events which often up-regulate an expression of an oncogene, the most famouse being the the philadelphia chromosome and this is by fusing the gene with a promotor region that is always switched on or active.

Question 18

Describe the role of the MYC family of oncogenes

Answer 18

• In the MYC family of oncogenes we see amplification
• This means that there are 10 to 100 copies of an oncogene sequence
• This may be an amplification of a large chromosome region detectable by microscopy of a smaller region around the gene
• Multiple copies of the oncogene leads to increased expression of the protein

Question 19

Describe the role of the RAS oncogene family

Answer 19

• In the RAS oncogene family, we see a point mutation
• This leads to an alteration in the coding sequence and thus altered sequence in the protein
• There is a qualitative difference in the expressed protein

Question 20

Provided 3 examples of oncogenes with different mechanims to mutate or activate them and describe these mechanisms

Answer 20

1. Philadelphia chromosome - chromosomal translocation events often up-regulate an expression of an oncogene, most famous being the philadelphia chromosome, by fusing the gene with a promoter region that is always switched on or active
2. MYC family of oncogenes - we see amplification of oncogenes which lads to increased expression of the protein
3. RAS oncogene family - point mutation leading to qualitative difference in the expressed protein

Question 21

Describe the relationship between the philadelphia chromosome and leukaemia’s

Answer 21

• The Philadelphia chromosome has specific regions of chromosome 9 and 22 translocated which causes chronic myeloid leukaemia (CML)
• The Ph chromosome occurs in a bone marrow stem cell, from which all blood cells have the potential to derive
• The fusion gene resulted, bcr-abl causes the malignant phenotypes associated with leukaemia

Question 22

a) What is the normal role of proteins of a tumour suppressor gene?
b) How many alleles require a loss of function for there to be an effect on proteins of tumour supressor genes
c) Name 2 improtant tumour supressor genes

Answer 22

a) Normal role of tumour suppressor genes is to restrain uncontrolled cell divison i.e., halting the cell cycle so DNA can be repaired or triggering apoptosis in response to DNA damage
b) Normally a loss of function is required in bot alleles to have an effect (reccessive)

c)

1. TP3 gene encoding for p53 protein
2. Retinoblastoma (Rb) gene

Question 23

What is the function of the retinoblastoma (Rb) gene in the cell cycle?

Answer 23

• Retinoblastoma regulates the progression from G1 to the S phase of the cell cycle
• The E2F transcription factor is released when retinoblastoma is phospharylated by the CDK4/cyclin D complex
• Retinoblastoma mutation results constituctively free E2F allowing progression from the cell cycle and uncontrolled growth of cells

Question 24

a) What is retinoblastoma
b) Describe how it is caused
c) Describe the inherited and sporadic (irregular or random instances) form of the disease and how it is brought about

Answer 24

a) Retinoblastoma is a human childhood disease, involving a tumour of the retina
b) It caused by loss of both copies of the RB gene on chromosome 13. The RB gene normally produces a protein (E2F) that interacts with components in the cell cycle, bocking the controlled prolifertion of cells. A ‘loss-of-function’ mutation in the RB1 gene can lead to permanent inactivation, allowing uncontrolled cell division
c) In the inherited form of the disease, one chromosome has a deletion, and the second copy is lost by a somatic mutation (mutation after conception). Therefore, parents are normal, 50% of offspring inherit the disease and there are several tumours, affecting both eyes

In the sporaic form of the disease both copies are lost by somatic mutation events (an event that occus after conception). Therefore, parents are unaffected, no risk to offspring and single tumour affecting only on eye.

Question 25

Describe the normal function of TP3 gene and p53 protein

Answer 25

• TP3 gene provides instructions that codes for tumour protein 53 (p53)
• If DNA is damaged in the G1 phase thistriggers the expression of the p53 gene which stops the cell from eneterig the S phase of the cycle to allow DNA repair to take place
• p53 stops the cycle by causing transcription of cyclin-dependant kinase inhibitors called p21
• p21 blocks the CDK4/Cyclin D complex
• If the DNA damage is so severe that it cannot be repaired p53 can stop the cycle or can cause senescence and if it’s too severe it can trigger apoptosis

Question 26

Describe TP3 and its role in Li Fraumeni syndrome

Answer 26

• Li Fraumeni syndrome is a rare autosomal disorder caused by inherited mutations of TP53
• It is characterised by a familial clustering of early onset tumours (<45 yrs.)
• Predominance of sarcomas, breast cancers, brain tumours and adrenocortical carcinomas

Question 27

List the 6 main risk factors of cancer

Answer 27

1. Smoking
2. Obesity
3. Alcohol
4. UV radiation
5. Physical inactivity
6. Poor diet

Question 28

Germline mutations can increase cancer isk.

a) Why must they be identified?
b) What may a patient be offered?

Answer 28

a) These germline variants need to be identified as it can have implication for their clinical care
b) A patient may be offered additional screening or prohylactic surgery

Question 29

Carcinogens may bechemicals, infectious agents, or different forms of radiation. There are two classes of carcinogens. Describe the two classes.

Answer 29

1. Initiators - predispose cells to develop tumours
2. Promoters - stimulate tumour development

Question 30

List examples of carcinogens

Answer 30

• Tobacco smoke
• Ionising raditation
• Aflatoxin (toxin produced by mould that grows on peanuts)
• Alcohol
• Asbestos
• Benzene
• Bracken
• Charred foods
• Creosote
• Diesal fumes
• Dioxins
• Radon
• Formaldehyde
• Saccharin
• Tar
• HPV
• Human T-cell lymphotropic virus

Question 31

The incidence of cancers increases with ages. What is a notacable exception of this?

Answer 31

Testicular cancer

Question 32

Explain how obesity can cause cancer

Answer 32

1. Fat cells make extra hormones and growth factors
2. Hormones and growth factors tell cells in our body to divide more often
3. This increases the chance of cancer cells being produced
4. This can divide and cause a tumour